EP2411373B1 - Procede de preparation d'erlotinib ou de ses sels pharmaceutiquement acceptables - Google Patents

Procede de preparation d'erlotinib ou de ses sels pharmaceutiquement acceptables Download PDF

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Publication number
EP2411373B1
EP2411373B1 EP10713723.4A EP10713723A EP2411373B1 EP 2411373 B1 EP2411373 B1 EP 2411373B1 EP 10713723 A EP10713723 A EP 10713723A EP 2411373 B1 EP2411373 B1 EP 2411373B1
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Prior art keywords
erlotinib
formula
acid
methoxyethoxy
bis
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EP2411373A1 (fr
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Balaguru Murugesan
Anandam Vempali
Swargam Sathyanarayana
Rajesh Kumar Thaper
Mohan Prasad
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the present invention relates to a process for the preparation of erlotinib of Formula I or its pharmaceutically acceptable salt thereof.
  • Erlotinib of Formula I chemically N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) -4-quinazolinamine, is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen, and in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.
  • Erlotinib is administered as its hydrochloride salt and is currently marketed as TARCEVA® (erlotinib) tablets.
  • Erlotinib hydrochloride has the molecular formula C 22 H 23 N 3 O 4 .HCl and a molecular weight of 429.90. It is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.
  • European Patent No. EP 0 817 775 provides a process for the preparation of erlotinib, which involves adding 3-ethynylaniline and 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline in isopropanol containing pyridine, and then refluxing the mixture for 4 hours under the atmosphere of dry nitrogen. The solvent is removed and residue is extracted in 10% methanol in chloroform and saturated aqueous sodium bicarbonate.
  • N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine base is separated chromatographically and converted to the hydrochloride salt in a solvent, such as, chloroform using hydrochloric acid.
  • erlotinib acid-addition salt for example, erlotinib salt with an inorganic or organic acid, such as, hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulfonic, benzenesulfonic, trifluoroacetic, citric, lactic or maleic acid, it only exemplifies the process for the preparation of erlotinib hydrochloride.
  • an inorganic or organic acid such as, hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulfonic, benzenesulfonic, trifluoroacetic, citric, lactic or maleic acid
  • European Patent No. EP 1 044 969 provides a process for preparing N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine which involves stirring 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol with anhydrous sodium hydroxide and 2-methoxyethanol and heating at reflux for 47 hours. The reaction mixture is cooled to 20°C to 25°C and concentrated hydrochloric acid is added to it. The resulting mixture is granulated at 20°C to 25°C to crystallize the product.
  • PCT Publication No. WO 2008/122776 A2 (herein after "the WO '776 application") provides a process for the preparation of erlotinib salts, such as, erlotinib hydrochloride, erlotinib sulphate, erlotinib tosylate and erlotinib oxalate by reacting 4-halo-6,7-bis(2-methoxyethoxy)quinazoline with 3-aminophenyl acetylene or an acid salt thereof under acidic conditions to give corresponding acid salt of erlotinib.
  • erlotinib salts such as, erlotinib hydrochloride, erlotinib sulphate, erlotinib tosylate and erlotinib oxalate by reacting 4-halo-6,7-bis(2-methoxyethoxy)quinazoline with 3-aminophenyl acetylene or an acid salt thereof under acidic
  • PCT Publication WO 2007/138612 provides a process for preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride which involves reacting 3,4-dihydroxy benzaldehyde with substituted ethylmethyl ether in the presence of an inert solvent and base to obtain 3,4-bis(2-methoxyethoxy) benzaldehyde.
  • the 3,4-bis(2-methoxyethoxy) benzaldehyde is converted to 3,4-bis(2-methoxyethoxy) benzaldoxime in the presence of a base and organic solvent and is further dehydrated to 3,4-bis(2-methoxyethoxy) benzonitrile.
  • the benzonitrile so obtained is nitrated to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile which is further reduced to obtain 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile.
  • N'-(3-ethynylphenyl)-N,N-dimethyl formamidine obtained by formylation of 3-ethynylaniline with N,N-dimethyl formamidine is coupled with 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile to obtain erlotinib free base which upon treatment with a polar solvent containing hydrochloric acid gives erlotinib hydrochloride.
  • PCT Publication WO 2007/138613 provides a process for preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride which involves reacting 3,4-dihydroxy benzaldehyde with substituted ethylmethyl ether in the presence of an inert solvent and base to obtain 3,4-bis(2-methoxyethoxy) benzaldehyde.
  • the 3,4-bis(2-methoxyethoxy) benzaldehyde is converted to 3,4-bis(2-methoxyethoxy) benzaldoxime in the presence of a base and organic solvent and is further dehydrated to 3,4-bis(2-methoxyethoxy) benzonitrile.
  • the benzonitrile so obtained is nitrated to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile which is further reduced to get 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile.
  • 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile is formylated with N,N-dimethyl formamidine to obtain N'-[2-cyano-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine which is coupled with an 3-ethynylaniline to obtain erlotinib free base which on treatment with a polar solvent containing hydrochloric acid gives erlotinib hydrochloride.
  • J.Chem. Soc., Perkin Trans. 2, 2000, 2498-2502 provides process for the preparation of erlotinib mesylate by treating erlotinib hydrochloride in water-ethylacetate with 50% aqueous sodium hydroxide solution at 50°C and separating organic layer, filtering through short pad of celite, the resulting solution is warmed to 50°C to redissolve precipitated free base, followed by treating the solution with methane sulphonic acid to give a white precipitate, which upon cooling for 4 hours gives erlotinib methane sulphonate.
  • the present inventors have found a process for the preparation of erlotinib or its pharmaceutically acceptable salt thereof, which involves preparing erlotinib or its pharmaceutically acceptable salt thereof directly from 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile and avoiding the usage of corrosive chemicals, such as, phosphorus oxychloride/thionyl chloride.
  • the process includes treating 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile of Formula II, with 3-ethynyl aniline of Formula III and a compound of Formula IV HC(OR) 3 Formula IV wherein R is alkyl group. wherein the process is carried out in a single step.
  • Embodiments of the present aspect may include one or more of the following features.
  • the process may further include the addition of an acid catalyst selected from the group comprising of acetic acid, trifluroacetic acid, formic acid.
  • the process may also include heating the mixture obtained to reflux at a temperature in the range of 30°C to 135°C.
  • the alkyl group of compound of Formula IV may include 1 to 6 carbon atoms.
  • the compound of Formula IV may be triethyl orthoformate.
  • the pharmaceutically acceptable salts of erlotinib may be prepared by treating erlotinib with an acid in a suitable solvent.
  • the present invention provides a process for preparing erlotinib or its pharmaceutically acceptable salt thereof which comprises treating 2-amino-4,5-bis (2-methoxyethoxy) benzonitrile of Formula II, with 3-ethynyl aniline of Formula III and a Compound of Formula IV HC(OR) 3 Formula IV wherein R is alkyl group, wherein the process is carried out in a single step.
  • alkyl as used herein, unless otherwise indicated, means an aliphatic hydrocarbon group which may be straight or branched and comprising 1 to 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as, methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • the 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile may be obtained by any of the methods known in the art including those described in WO 2007/138612 .
  • the 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile may be taken as a solution.
  • the solution of 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile may be obtained by dissolving 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile in an organic solvent.
  • the solvent used for the dissolution of 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile include alcohols, such as, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol; aromatic hydrocarbon, such as, benzene, toluene, and xylene, substituted toluenes, substituted xylenes; halogenated hydrocarbons, such as, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, chloroform, carbon tetrachloride; ethers, such as, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran;
  • the amount of organic solvent employed in the reaction depends on the homogeneity and stirring conditions of the reaction mixture.
  • the solution of 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile may be added to a solution of 3-ethynyl aniline and a compound of Formula IV, HC(OR) 3 Formula IV wherein R is alkyl group.
  • the solution of 3-ethynyl aniline and a compound of Formula IV, HC(OR) 3 Formula IV wherein R is alkyl group may further contain an acid catalyst, such as, acetic acid, trifluroacetic acid, formic acid.
  • an acid catalyst such as, acetic acid, trifluroacetic acid, formic acid.
  • the mixture may also be obtained by adding 2-amino-4, 5-bis(2-methoxyethoxy) benzonitrile; 3-ethynyl aniline; a compound of Formula IV and an acid catalyst in optional order of succession.
  • the mixture obtained may be stirred and after stirring may be heated to reflux at a temperature in the range of 30°C to 135°C for about 3 hours to about 24 hours.
  • the reaction mass may be cooled to room temperature and the pH may be adjusted to about 3.0 to about 4.0 with a suitable acid in a suitable solvent.
  • erlotinib may be prepared by treating erlotinib base with a corresponding acid in a suitable solvent.
  • Suitable pharmaceutically acceptable salts of erlotinib include salts of erlotinib base with acetic acid, benzoic acid, fumaric acid, benzoic acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, hydrochloric acid, hydrobromic acid and sulfuric acid.
  • Suitable solvent include alcohols, such as, methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol; aromatic hydrocarbon, such, as benzene, toluene, and xylene, substituted toluenes, substituted xylenes; halogenated hydrocarbons, such as, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, chloroform, carbon tetrachloride; ethers, such as, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran; ketones, such as, acetone, methyl ethyl ketone, methyl isobutyl ketone; alkyl acetate, such as, ethyl acetate, n-

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (6)

  1. Procédé de préparation d'erlotinib de Formule 1 ou de ses sels pharmaceutiquement acceptables,
    Figure imgb0013
     le procédé comprenant le traitement de 2-amino-4,5-bis(2-méthoxyéthoxy)benzonitrile de Formule II
    Figure imgb0014
     avec de la 3-éthynylaniline de Formule III
    Figure imgb0015
     et un composé de Formule IV

            HC(OR)3     Formule IV

    où R est un groupe alkyle.
  2. Procédé selon la revendication 1, comprenant en outre l'addition d'un catalyseur acide choisi dans le groupe comprenant l'acide acétique, l'acide trifluoroacétique et l'acide formique.
  3. Procédé selon la revendication 1, le procédé comprenant en outre le chauffage à reflux du mélange obtenu à une température comprise entre 30 °C et 135 °C.
  4. Procédé selon la revendication 1, dans lequel le groupe alkyle du composé de Formule IV comprend 1 à 6 atomes de carbone.
  5. Procédé selon la revendication 4, dans lequel le composé de Formule IV est l'orthoformiate de triéthyle.
  6. Procédé selon la revendication 1, dans lequel les sels pharmaceutiquement acceptables d'erlotinib sont préparés par traitement de l'erlotinib avec un acide dans un solvant approprié.
EP10713723.4A 2009-03-26 2010-03-26 Procede de preparation d'erlotinib ou de ses sels pharmaceutiquement acceptables Active EP2411373B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN596DE2009 2009-03-26
IN483DE2010 2010-03-04
PCT/IB2010/051343 WO2010109443A1 (fr) 2009-03-26 2010-03-26 Procede de preparation d'erlotinib ou de ses sels pharmaceutiquement acceptables

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EP2411373B1 true EP2411373B1 (fr) 2015-10-21

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HU230483B1 (hu) * 2011-10-10 2016-07-28 Egis Gyógyszergyár Nyrt. Erlotinib sók
CN102887862A (zh) * 2012-07-24 2013-01-23 连云港盛和生物科技有限公司 厄洛替尼的合成方法
US9593083B2 (en) 2012-09-04 2017-03-14 Shilpa Medicare Limited Crystalline erlotinib hydrochloride process
WO2014118737A1 (fr) 2013-01-31 2014-08-07 Ranbaxy Laboratories Limited Sels d'erlotinib
CN103396371B (zh) * 2013-08-26 2015-12-02 南京优科生物医药研究有限公司 一种盐酸埃罗替尼晶型a的制备方法
CN103739558B (zh) * 2013-09-23 2016-05-04 南京优科生物医药研究有限公司 一种吉非替尼已知杂质的制备方法
CN104003946B (zh) * 2014-03-17 2016-01-06 宁波美诺华药业股份有限公司 一种盐酸厄洛替尼杂质的制备方法
EP3154951A4 (fr) * 2014-06-10 2017-12-06 Scinopharm (Changshu) Pharmaceuticals Ltd. Procédé de préparation de dérivé de quinazoline
CN104059026B (zh) * 2014-06-20 2016-03-30 凯莱英医药集团（天津）股份有限公司 一种制备盐酸厄洛替尼的方法
CA2908441A1 (fr) * 2014-10-28 2016-04-28 Cerbios-Pharma Sa Procede de preparation d'erlotinib
CN105646374B (zh) * 2015-12-31 2018-11-27 山东罗欣药业集团恒欣药业有限公司 一种盐酸厄洛替尼的制备方法
CN106832059B (zh) * 2017-03-08 2019-01-18 福州大学 一种具有肿瘤靶向性的厄洛替尼-Cy7-壳聚糖聚合物
WO2020165672A1 (fr) 2019-02-15 2020-08-20 Shivalik Rasayan Limited Procédé de préparation de chlorhydrate de fingolimod pur

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WO2009025875A1 (fr) 2007-08-23 2009-02-26 Plus Chemicals Sa Formulations stables de chlorhydrate d'erlotinib cristallin

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CN102438995A (zh) 2012-05-02
CN102438995B (zh) 2014-12-17
US20120101272A1 (en) 2012-04-26
US8440823B2 (en) 2013-05-14
WO2010109443A1 (fr) 2010-09-30
EP2411373A1 (fr) 2012-02-01

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